The ability of a substance to exist in more than one crystalline form is defined as polymorphism and these different crystalline forms are named “polymorphs”. In general, polymorphism is caused by the ability of the molecule of a substance to change its conformation or to form different intermolecular and intramolecular interactions giving different atom arrangements that is reflected in the crystal lattices of different polymorphs. However, polymorphism is not a universal feature of solids, since some molecules can exist in one or more crystal forms while other molecules cannot. Therefore, prediction of polymorphism remains a highly unpredictable art.
The different polymorphs of a substance posses different energies of the crystal lattice and thus each polymorph typically shows one or more different physical properties in the solid state, such as density, melting point, color, stability, dissolution rate, flowability, compatibility with milling, granulation and compacting and/or uniformity of distribution (See, e.g., P. DiMartino, et al., J. Thermal Anal. 48:447 458 (1997)). The capacity of any given compound to occur in one or more crystalline forms (i.e. polymorphs) is unpredictable as are the physical properties of any single crystalline form. Different physical properties of a substance may affect the ability to prepare different pharmaceutical formulations comprising the substance and may also affect the stability, dissolution and bioavailability of a solid-state formulation, which subsequently affects suitability or efficacy of such formulations in treating disease.
Therefore, knowledge of polymorphism of a compound for use in preparing a composition, such as a pharmaceutically acceptable formulation to treat a disease in a subject, can sometimes affect the development of a medicament. On the basis of this knowledge, an individual polymorph having one or more desirable properties can be selected for the development of a pharmaceutical formulation having the desired property(ies).
In the case of a chemical substance that exists in more than one polymorphic or pseudo-polymorphic form, a less thermodynamically stable form can occasionally convert to the more thermodynamically stable form at a given temperature after a sufficient period of time. When this transformation is not rapid, such a thermodynamically unstable form is referred to as a “metastable” form. In some instances, the stable form exhibits the highest melting point, the lowest solubility, and the maximum chemical stability. In other cases, the metastable form may exhibit sufficient chemical and physical stability under normal storage conditions to permit its use in a commercial form. In this case, the metastable form, although less thermodynamically stable, may exhibit properties desirable over those of the stable form, such as enhanced solubility or better oral bioavailability. Likewise a non-crystalline material may have enhanced solubility in comparison to its crystalline forms due to reduction or absence of crystal lattice forces that must be overcome to effect dissolution of these materials.